Association of hyperglycaemia at-admission & diabetes mellitus with 28 day mortality in patients admitted with moderate-severe SARS-CoV-2 infection: A retrospective study.

Background & objectives: The association between hyperglycaemia at admission, diabetes mellitus (DM) status and mortality in hospitalized SARS-CoV-2 infected patients is not clear. The purpose of this study was to determine the relationship between DM, at-admission hyperglycaemia and 28 day mortality in patients admitted with moderate-severe SARS-CoV-2 infection requiring intensive care. Methods: All consecutive moderate-to-severe patients with SARS-CoV-2 infection admitted to the intensive care units (ICUs) over six months were enrolled in this single-centre, retrospective study. The predicators for 28 day mortality were analysed from the independent variables including DM status and hyperglycaemia at-admission. Results: Four hundred and fifty two patients with SARS-CoV-2 were admitted to the ICU, with a mean age of 58.5±13.4 yr, 78.5 per cent being male, HbA1c of 7.2 per cent (6.3-8.8) and 63.7 per cent having DM. Overall, 28 day mortality was 48.9 per cent. In univariate analysis, mortality in diabetes patients was comparable with non-diabetes (47.9 vs. 50.6%, P=0.58), while it was significantly higher in hyperglycaemic group (60.4 vs. 35.8%, P<0.001). In multivariate Cox regression analysis, after adjusting for age, sex and comorbidities, hyperglycaemia at-admission was an independent risk factor of mortality [hazard ratio (HR) 1.45, 95% confidence interval (CI) (1.06-1.99), P<0.05]. Interpretation & conclusions: This study showed that the presence of hyperglycaemia at-admission in critically ill SARS-CoV-2 patients was an independent predictor of 28 day mortality. However, the findings may be susceptible to unmeasured confounding, and more research from prospective studies is required.

High prevalence of idiopathic (islet antibody-negative) type 1 diabetes among Indian children and adolescents.

OBJECTIVES: To study the prevalence and clinical characteristics of islet antibody-negative (idiopathic) type 1 diabetes mellitus (T1DM) among Indian children and adolescents at the time of diagnosis of illness. METHODS: In a hospital-based cross-sectional study, we studied 110 patients with T1DM aged ≤18 years. This included 61 patients with duration of diabetes ≤2 weeks (mean ± SD age of onset 9.9 ± 4.4 years) and 49 patients with duration 2 to 12 weeks. Antibodies against GAD65 (GADA), IA-2 (IA-2A) and zinc transporter 8 (ZnT8A), detected by radio-binding assay, were measured in all patients. Insulin autoantibody (IAA) was measured only in subjects with duration ≤2 weeks, using a competitive radio-binding assay. RESULTS: The prevalence of GADA, IA-2A, and ZnT8A was 53%, 34%, and 29% respectively, while IAA (measured in 61 patients) was detected in 31%. All four antibodies were absent in 17 of 61 (28%) patients. The prevalence of islet antibody-negative patients was similar among both sexes and in children with onset younger and older than 10 years. ZnT8A was the only antibody detected in four patients, and its measurement resulted in 6% reduction in islet antibody-negative patients. Patients with idiopathic T1DM did not differ in their clinical features or fasting plasma C-peptide at the onset and after follow-up of 1 year. Compared with idiopathic T1DM, antibody-positive patients had an increased allele frequency of HLA DRB1*0301 (46% vs 14%, OR = 5.10 [confidence interval = 1.61-16.16], P = .003). CONCLUSION: Nearly 30% of Indian patients were negative for all islet antibodies at the onset of T1DM. Patients with idiopathic T1DM had similar clinical features to antibody-positive subjects.

Hereditary Medullary Thyroid Carcinoma: Genotype, Phenotype and Outcomes in a North Indian Cohort.

BACKGROUND: Aggressiveness of hereditary medullary thyroid carcinoma (hMTC) has been conventionally described to correlate with American Thyroid Association (ATA) risk groups based on RET mutations. Recent evidence increasingly contradicts this notion. We studied the RET genotype and its correlation with disease phenotype and survival outcomes in a cohort of hMTC patients. METHODS: In a retrospective cohort of 55 hMTC patients from 23 families treated at a north Indian tertiary care institute over 15-years, RET genotype was correlated with disease phenotype (clinical, biochemical, and pathological attributes) and outcomes in terms of biochemical cure (normalization of serum calcitonin), structural cure, overall survival (OS) and disease specific survival (DSS). RESULTS: Forty-nine patients had Multiple Endocrine Neoplasia (MEN)-type 2A syndrome, 02 had MEN-2B, and 4 had familial MTC. Two patients belonged to highest ATA risk, 41 to high-risk, and 12 to moderate risk categories. Age of the patients or stage of disease at presentation did not differ significantly between the ATA risk groups. Though the baseline serum calcitonin was significantly higher in highest risk category, the biochemical cure rates were not significantly different. At a median follow up of 48 months (Inter-quartile range 18-84, range 12-192) structural cure rates in ATA moderate and high risk groups were significantly higher than highest risk group (p = 0.04). No significant difference in OS between the three ATA groups of hMTC among the patients who underwent surgical treatment was observed (p = 0.098). CONCLUSIONS: The ATA moderate and high risk groups have better structural cure rates compared to ATA highest risk group. The biochemical cure and overall survival rates did not significantly differ between ATA risk-groups, and were impacted by the disease stage at presentation. The current ATA risk-groups do not reliably predict the outcomes in terms of biochemical cure and survival in hMTC patients.

Low Diagnostic Utility of Overnight High-Dose Dexamethasone Suppression Test in ACTH-Dependent Cushing's Syndrome.

OBJECTIVE: Overnight high-dose dexamethasone suppression test (ON-HDDST) is a simple test to localize the source of ACTH in patients with ACTH-dependent Cushing's syndrome (CS). However, previous studies have reported its varying accuracy. We studied the utility of ON-HDDST in diagnosing Cushing's disease (CD) in a series of patients with CD and ectopic ACTH syndrome (EAS). METHODS: We conducted a retrospective study of 88 patients with ACTH-dependent CS (plasma ACTH > 20.0 pg/mL), who underwent an ON-HDDST. CD and EAS were diagnosed in 68 and 20 patients, respectively. Patients were investigated using MRI of the sellar region, CT of the thorax/abdomen, Gallium-68-DOTANOC PET scan, and bilateral inferior petrosal sinus sampling as required. RESULTS: Patients with EAS had a significantly higher serum cortisol after ON-HDDST than patients with CD (median [IQR], 19.9 [12.4-31.1] µg/dL vs 9.9 [5.1-25.0] µg/dL, P <.01). A suppressed ON-HDDST (≥50% fall from baseline) was noted in 44 (65%) patients with CD and 3 (15%) patients with EAS (P <.0001). Among patients with CD, cortisol suppression >50% was noted in 35 (76%) of patients with microadenoma and 7 (44%) with macroadenoma. Among patients with EAS, ON-HDDST was suppressed in 1 of 6 patients (17%) with an occult tumor and 2 of 14 patients (14%) with a localized tumor. The ROC curve plotted for the percentage suppression of cortisol had an area under the curve (AUC) of 0.72 (P =.01). The best test parameters, with 65% sensitivity, 85% specificity, 94% positive predictive value, 42% negative predictive value, and 69% accuracy, were at 50% cutoff level. CONCLUSION: The ON-HDDST had a poor diagnostic value in differentiating CD and EAS.

Clinical outcomes and cortical reserve in adrenal histoplasmosis-A retrospective follow-up study of 40 patients.

OBJECTIVE: Detailed studies of Addison's disease resulting from disseminated adrenal histoplasmosis (AH) are not available. We describe the presentation and prognosis of AH and cortisol status before and after antifungal therapy. DESIGN: Single-centre retrospective hospital-based study of 40 consecutive adults with AH [39 males; age (mean ± SD) 53 ± 11 years] was conducted between 2006 and 2018. The median duration of follow-up was 2.5 years (range 0.2-12 years). PATIENTS AND METHODS: AH was diagnosed by bilateral adrenal enlargement on CT scan and presence of Histoplasma by histology and/or culture of biopsied adrenal tissue. All patients received oral itraconazole and, if required, amphotericin B as per guidelines. ACTH-stimulated serum cortisol (normal > 500 nmol/L) was measured in 38 patients at diagnosis and re-tested after one year of antifungal therapy in 21 patients. RESULTS: Seventy-three per cent of patients had primary adrenal insufficiency (PAI) and one-third had an adrenal crisis at presentation. HIV antibody was negative in all patients. Of the 29 patients who completed antifungal therapy, 25 (86%) were in remission at last follow-up. Overall, 8 (20%) patients died: three had a sudden death, four had severe histoplasmosis and one died due to adrenal crisis. No patient with PAI became eucortisolemic on re-testing after one year of antifungal therapy. Of the eight patients with normal cortisol at diagnosis, two developed adrenal insufficiency on follow-up. CONCLUSION: All patients with AH tested negative for HIV antibody. While patients achieved a high rate of clinical remission after antifungal therapy, overall mortality was significant. Cortisol insufficiency did not normalize despite treatment.

Decreased bone mineral density in women with Sheehan's syndrome and improvement following oestrogen replacement and nutritional supplementation.

Sheehan's syndrome (SS) is an important cause of pan-hypopituitarism in women. There is scanty information on bone mineral density (BMD) in this condition. We determined BMD and the changes in BMD after oestrogen (E2) replacement and nutritional supplementation in women with SS. In a cross-sectional study, BMD was measured by DEXA in 83 patients [age (mean ± SD) 42 ± 9.2 years] and compared with an equal number of matched controls. In a sub-set of 19 patients, we conducted an open-label, prospective study to determine changes in BMD after 1 year of replacement of E2, and calcium and vitamin D3 supplementation. All patients had low serum IGF-1 and E2, while 98% had ≥ 3 pituitary hormone deficiencies. Compared with Indian reference standards, 47% had decreased bone mass (Z-score ≤ - 2.0). BMD Z-scores were decreased at all sites, being most marked in the lumbar spine and femoral neck. At the lumbar spine, BMD was lowest among the age group 21-30 years. Women with SS also had significantly lower BMD Z-scores at all three sites on comparison with ethnic controls. On multivariate analysis, BMD Z-score was associated with weight, daily calcium intake and age (lumbar spine). In the prospective study, 1 year of therapy improved BMD Z-score at lumbar spine (- 1.4 ± 1.2 vs. - 1.1 ± 1.1, p = 0.02), but not at hip or femoral neck. In conclusion, patients with SS had significantly lower BMD compared to controls at all three sites. Replacement of E2 and supplementation with calcium/vitamin D3 lead to significant improvement in lumbar spine BMD.

The impact of free medical supplies and regular telephonic contact on glycemic control in Indian children and adolescents with type 1 diabetes.

BACKGROUND/OBJECTIVE: The effect of economic assistance to underprivileged families with type 1 diabetes has never been described. Such a study is relevant as logistic and cultural factors may preclude an anticipated good outcome. The objective of the study is to determine the impact of economic and educational intervention on hemoglobin A1c (HbA1c) and diabetes knowledge. METHODS: Eighty-five consecutive participants were prospectively provided insulin and glucose strips for 1 year. From the 6th to 12th month, patients were randomized such that half of them (telephone group) received proactive telephonic advice by a diabetes educator, while the non-telephone group received usual care. HbA1c and diabetes knowledge were measured at baseline, 6 and 12 months. RESULTS: Significant improvement was seen in HbA1c with provision of free diabetes supplies, when patients were compared with their own HbA1c values during the prior 36 months (baseline [8.38 ± 2.0%], at 3 months [8.0 ± 1.6%] and at 6 months [8.1 ± 1.5%, P = 0.0106]). Knowledge score increased from baseline (48 ± 15) to 6 months (58 ± 13, P < 0.001). No difference was seen between the telephone and non-telephone groups in HbA1c from the 6th to 9th and 12th month. The knowledge score showed significant improvement in the telephone group during the proactive telephonic advice study compared with the non-telephone group (P = 0.002). CONCLUSIONS: The provision of free medical supplies improved HbA1c and diabetes knowledge. Intensive telephone contact improved knowledge, not HbA1c. These results provide important background for policy makers and diabetes management teams.

Heterogeneity in the aetiology of diabetes mellitus in young adults: A prospective study from north India.

Background & objectives: In contrast to Caucasians of European origin, the aetiology of diabetes mellitus (DM) in young adults in other ethnic groups, including Indians is likely to be heterogeneous and difficult to determine. This study was undertaken to determine the aetiology of diabetes in young Indian adults using a protocol-based set of simple clinical and investigation tools. Methods: In this prospective study, 105 Indian young adults with diabetes (age at onset 18-35 yr; duration <2 yr) were studied for a period of 1-3 years. Pancreatic imaging, fasting C-peptide, islet antibodies (against glutamic acid decarboxylase, tyrosine phosphatase and zinc transporter-8) and mitochondrial A3243G mutational analysis were performed in all patients. Four patients were screened for maturity-onset diabetes of the young (MODY) using next-generation sequencing. Results: Type 1 and type 2 diabetes mellitus (T1DM and T2DM) were equally frequent (40% each), followed by fibrocalculous pancreatic diabetes (FCPD, 15%). Less common aetiologies included MODY (2%), mitochondrial diabetes (1%) and Flatbush diabetes (2%). There was considerable phenotypic overlap between the main aetiological subtypes. Elevated islet antibodies were noted in 62 per cent of T1DM patients [positive predictive value (PPV) 84%; negative predictive value (NPV) 78%] while low plasma C-peptide (<250 pmol/l) was present in 56 per cent of T1DM patients [PPV 96% (after excluding FCPD), NPV 72%]. Using these tests and observing the clinical course over one year, a final diagnosis was made in 103 (99%) patients, while the diagnosis at recruitment changed in 23 per cent of patients. Interpretation & conclusions: The aetiology of diabetes in young adults was heterogeneous, with T1DM and T2DM being equally common. FCPD was also frequent, warranting its screening in Indian patients. Testing for islet antibodies and C-peptide in this age group had good PPV for diagnosis of T1DM.

Identification of autoimmune polyendocrine syndrome type 1 in patients with isolated hypoparathyroidism.

OBJECTIVE: The prevalence of autoimmune polyendocrine syndrome type 1 (APS1) among isolated hypoparathyroidism (HP) or primary adrenal insufficiency (PAI) is not well established. We studied the frequency of APS1 in patients with HP or PAI by measuring interferon-α (IFN-α) antibody levels, a highly sensitive and specific marker for APS1. DESIGN, PATIENTS AND MEASUREMENTS: In a single-centre cross-sectional study, 37 Indian patients with isolated HP and 40 patients with PAI were tested for IFN-α antibody using an indirect ELISA. In patients with elevated IFN-α antibody, the autoimmune regulator (AIRE) gene was bidirectionally sequenced. RESULTS: Three (8·1%) patients with isolated HP had elevated IFN-α antibody levels (range: 367-17382 units; positive titre >56 units). Homozygous or compound heterozygous AIRE mutations were detected in all three patients, including a novel mutation (p.T68P). All three APS1 patients had atypical features. The first patient, diagnosed at 7 years of age, died suddenly 5 months later. The second patient had late-onset HP (at the age of 34 years) and a solitary episode of transient mucocutaneous candidiasis 5 years later. The final patient developed HP at the age of 14 years and premature ovarian insufficiency 14 years later. Interleukin-22 antibodies, as well as most other organ-specific antibodies, were absent in the 3 APS1 patients. All patients with PAI were negative for IFN-α antibody. CONCLUSION: Eight percentage of patients with isolated HP had elevated IFN-α antibody levels and AIRE mutation-positive APS1. All APS1 patients had atypical clinical features. Testing for IFN-α antibody should be considered in patients with idiopathic HP.

Genotype-Phenotype Correlation in Indian Patients with MEN2-Associated Pheochromocytoma and Comparison of Clinico-Pathological Attributes with Apparently Sporadic Adrenal Pheochromocytoma.

INTRODUCTION: Pheochromocytoma (PCC) manifests in up to 50% of MEN2 patients. We correlated the clinico-pathological features of MEN2-associated PCC (MEN-PCC) with RET mutations and compared them with non-MEN adrenal-PCCs. METHODS: In this retrospective single institution study on a large PCC database (n = 208, 1997-2014) 24 MEN-PCC patients with known RET mutations were reviewed. Excluding 7 with incomplete data, the study cohort of 17 MEN-PCC patients from 11 kindreds (M:F::7:10) was identified. Clinical, biochemical, pathological attributes, and outcomes in the MEN-PCC group were correlated with the genotype, and further compared with non-MEN, apparently sporadic adrenal-PCCs (n = 132, excluding 37 extra-adrenal and 15 VHL/NF1/SDH-associated PCC). RESULTS: Components of MEN2 encountered included MTC in 13(76.5%), Marfanoid habitus in 2, and PHPT, cutaneous lichen amyloidosis and mucosal neuromas in 1 patient each. In 11(64.7%), PCC was the first detected MEN2 component (Symptomatic:8, Incidentaloma:3). Four (23.5%) were normotensive; 8(47.1%) had bilateral PCC (7 synchronous, 1 metachronous). Surgery for PCC included laparoscopic adrenalectomy in 12; and cortical-sparing adrenalectomy in 2 of 8 bilateral PCC patients. Mean MEN-PCC tumor size was 6.9 ± 3.9 cm, and 6(35%) had additional adrenal medullary hyperplasia. Four different genotypes were encountered, commonest involving codon 634, others being 804 and 918. Mean age in MEN-PCC (27.7 ± 12.2 years) was lower than non-MEN PCC (39.4 ± 15.7, p = 0.018). Proportion of pediatric patients (35.3% in MEN-PCC vs. 12.9% in non-MEN-PCC, p = 0.007), bilateral tumors (47.1% in MEN-PCC, 4.5% in non-MEN-PCC, p < 0.001), and adrenal medullary hyperplasia (35.2% in MEN-PCC, 0.7% in non-MEN-PCC, p < 0.001) were different. Median 24-hour urinary metanephrines was significantly higher in index MEN-PCC patients, than non-MEN-PCC (634 vs. 214 mcg/24 h, p value = 0.006), but was non-significantly higher in non-index MEN-PCC patients. Mean tumor sizes were comparable in the two groups. None of MEN-PCC patients had malignant PCC, compared to 7(5.3%) in non-MEN-PCC. CONCLUSIONS: In this cohort of MEN-PCC from India, the commonest causative RET mutations for MEN-PCC involved codon 634. MEN-PCC patients were younger, and more frequently had bilateral PCC than non-MEN disease. MEN-PCC patients in India are diagnosed with large tumors and extremely high catecholamine/metanephrine levels.

BONE MINERAL DENSITY IN PATIENTS WITH ADDISON DISEASE ON REPLACEMENT THERAPY WITH PREDNISOLONE.

OBJECTIVE: In primary adrenal insufficiency (PAI), replacement with prednisolone may result in lower bone mineral density (BMD) compared with hydrocortisone therapy. However, the number of patients studied on prednisolone is small and the results are conflicting. We conducted a cross-sectional study to determine BMD and its relation with therapy in patients on physiologic doses of prednisolone replacement. METHODS: Forty-one consecutive patients (31 males, age [mean ± SD] 50.9 ± 13.0 years), receiving prednisolone (hydrocortisone equivalent [HCE] 13.0 ± 3.0 mg/m(2)) for 104 ± 95 months were studied. BMD was evaluated by dual-energy X-ray absorptiometry and compared with an age- and sex-matched reference group of healthy Indian subjects (n = 677). RESULTS: Among males, BMD Z-scores (mean [95% confidence interval {CI}]) at lumbar spine (-0.42 [-0.80, -0.04]), femoral neck (-0.50 [-0.95, -0.06]) and total hip (-0.58 [-0.90, -0.26]) were significantly lower than the reference population. Z-scores in female patients did not differ from controls. Among postmenopausal females and males >50 years, 43% had osteoporosis (T-score ≤-2.5), as compared with 25% in the reference group (P = .04). There was no correlation between BMD Z-scores and HCE dose or duration of therapy. On multivariate regression analysis, body mass index was the only significant predictor of BMD. A high proportion of males (45%) had low serum testosterone (<300 ng/dL), but there was no correlation between testosterone and BMD. CONCLUSIONS: Male patients with PAI receiving physiologic prednisolone replacement had a small but significant diminution in BMD at all sites.

High direct costs of medical care in patients with Type 1 diabetes attending a referral clinic in a government-funded hospital in Northern India.

BACKGROUND: There is little information regarding costs of managing type 1 diabetes mellitus (T1DM) from low- and middle-income countries. We estimated direct costs of T1DM in patients attending a referral diabetes clinic in a governmentfunded hospital in northern India. METHODS: We prospectively enrolled 88 consecutive T1DM patients (mean [SD] age 15.3 [8] years) with age at onset <18 years presenting to the endocrine clinic of our institution. Data on direct costs were collected for a 12 months-6 months retrospectively followed by 6 months prospectively. RESULTS: Patients belonged predominantly (77%) to the middle socioeconomic strata (SES); 81% had no access to government subsidy or health insurance. The mean direct cost per patient-year of T1DM was `27 915 (inter-quartile range [IQR] `19 852-32 856), which was 18.6% (7.1%-30.1%) of the total family income. A greater proportion of income was spent by families of lower compared to middle SES (32.6% v. 6.6%, p<0.001). The mean out-of-pocket payment for diabetes care ranged from 2% to 100% (mean 87%) of the total costs. The largest expenditure was on home blood glucose monitoring (40%) and insulin (39.5%). On multivariate analysis, total direct cost was associated with annual family income (ß=0.223, p=0.033), frequency of home blood glucose monitoring (ß=0.249, p=0.016) and use of analogue insulin (ß=0.225, p=0.016). CONCLUSIONS: Direct costs of T1DM were high; in proportion to their income the costs were greater in the lower SES. The largest expenditure was on home blood glucose monitoring and insulin. Support for insulin and glucose testing strips for T1DM care is urgently required.

A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis.

Chronic pancreatitis is a common inflammatory disease of the pancreas. Mutations in the genes encoding cationic trypsinogen (PRSS1) and the pancreatic secretory trypsin inhibitor (SPINK1) are associated with chronic pancreatitis. Because increased proteolytic activity owing to mutated PRSS1 enhances the risk for chronic pancreatitis, mutations in the gene encoding anionic trypsinogen (PRSS2) may also predispose to disease. Here we analyzed PRSS2 in individuals with chronic pancreatitis and controls and found, to our surprise, that a variant of codon 191 (G191R) is overrepresented in control subjects: G191R was present in 220/6,459 (3.4%) controls but in only 32/2,466 (1.3%) affected individuals (odds ratio 0.37; P = 1.1 x 10(-8)). Upon activation by enterokinase or trypsin, purified recombinant G191R protein showed a complete loss of trypsin activity owing to the introduction of a new tryptic cleavage site that renders the enzyme hypersensitive to autocatalytic proteolysis. In conclusion, the G191R variant of PRSS2 mitigates intrapancreatic trypsin activity and thereby protects against chronic pancreatitis.

Prospective study to compare peri-operative hemodynamic alterations following preparation for pheochromocytoma surgery by phenoxybenzamine or prazosin.

BACKGROUND: Prospective studies comparing the efficacy of selective versus nonselective alpha blockers for preoperative preparation of pheochromocytoma (PCC) are lacking. In this prospective nonrandomized study, we compared the outcome of preoperative preparation with phenoxybenzamine (PBZ) and prazosin (PRZ) in terms of perioperative hemodynamic alterations. METHODS: The study was conducted at a tertiary referral center from July 2010 to December 2012. Thirty-two patients with PCC underwent operation after adequate preparation with PBZ (n = 15) or PRZ (n = 17). Five pediatric and adolescent patients were excluded because of different hemodynamics in this population. Perioperative monitoring was done for pulse rate (PR) and blood pressure(BP) alterations, occurrence of arrhythmias, and time taken to achieve hemodynamic stability. Groups were compared with the Mann-Whitney test, Student's t test, and the χ2 test as applicable. RESULTS: Patients in the two groups were similar in age,gender, 24 h urinary metanephrine and normetanephrine levels, and type of procedure. Patients prepared with PRZ had significantly more intraoperative episodes of transient hypertension (systolic BP ≥ 160 mmHg) and hypertensive urgency (BP >180/110 mmHg) (p 0.02, 0.03, respectively). More patients receiving PRZ suffered from transient severe hypertension (SBP ≥ 220 mmHg) (p 0.03). The PRZ group also had more median maximum SBP (233 mmHg vs PBZ 181.5 mmHg) (p = 0.01) and lesser median minimum SBP (71 mmHg vs PBZ 78 mmHg) (p 0.03). No significant differences were found between the study groups for changes in PR, postoperative BP alterations,occurrence of arrhythmias, and time taken to achieve hemodynamic stability. CONCLUSIONS: PBZ was found superior to PRZ in having fewer intraoperative hemodynamic fluctuations.

Prevalence of Graves' ophthalmopathy in patients with Graves' disease presenting to a referral centre in north India.

BACKGROUND & OBJECTIVES: The prevalence of Graves' ophthalmopathy (GO) varies widely in different ethnic groups. Indians have been reported to have a lower prevalence of Graves' ophthalmopathy as compared to Caucasians of European origin, but data are sparse and inconclusive. We studied the prevalence, clinical features and association of GO in Indian patients with Graves' disease attending a referral centre in north India. METHODS: A prospective study was conducted on 235 consecutive newly referred north Indian patients with Graves' disease presenting to a tertiary care centre in north India. All patients underwent a comprehensive ophthalmological examination as per the European Group on Graves' Orbitopathy (EUGOGO) recommendations. RESULTS: GO was diagnosed in 65 patients (prevalence 28%; 95% confidence interval 22-33%). The prevalence was similar in males (28%) and females (27%). It was mild in 83 per cent, moderate-severe in 15 per cent and sight-threatening in only 2 per cent of cases. Ophthalmopathy was clinically active in only two (3%) cases. Upper eyelid retraction was the most common manifestation (83%), followed by exophthalmos (75%). Extra-ocular muscle involvement (5%) and optic nerve dysfunction (2%) were uncommon. The risk of GO was 3.9- fold (95% confidence interval 1.1-13.6) higher in smokers compared to non-smokers. However, severity of disease in smokers was similar to non-smokers. On multivariate logistic regression analysis, GO was associated only with high thyrotropin receptor antibody titres and current smoking. INTERPRETATION & CONCLUSIONS: Among north Indian patients with GD studied at a referral center, the prevalence of GO was similar to Caucasians of European descent, but clinically active and severe ophthalmopathy was uncommon. More studies are needed to confirm these findings.

High Frequency of Recessive WFS1 Mutations Among Indian Children With Islet Antibody-negative Type 1 Diabetes.

BACKGROUND: While the frequency of islet antibody-negative (idiopathic) type 1 diabetes mellitus (T1DM) is reported to be increased in Indian children, its aetiology has not been studied. We investigated the role of monogenic diabetes in the causation of islet antibody-negative T1DM. METHODS: We conducted a multicenter, prospective, observational study of 169 Indian children (age 1-18 years) with recent-onset T1DM. All were tested for antibodies against GAD65, islet antigen-2, and zinc transporter 8 using validated ELISA. Thirty-four islet antibody-negative children underwent targeted next-generation sequencing for 31 genes implicated in monogenic diabetes using the Illumina platform. All mutations were confirmed by Sanger sequencing. RESULTS: Thirty-five (21%) children were negative for all islet antibodies. Twelve patients (7% of entire cohort, 34% of patients with islet antibody-negative T1DM) were detected to have pathogenic or likely pathogenic genetic variants. The most frequently affected locus was WFS1, with 9 patients (5% of entire cohort, 26% of islet antibody-negative). These included 7 children with homozygous and 1 patient each with a compound heterozygous and heterozygous mutation. Children with Wolfram syndrome 1 (WS) presented with severe insulin-requiring diabetes (including 3 patients with ketoacidosis), but other syndromic manifestations were not detected. In 3 patients, heterozygous mutations in HNF4A, ABCC8, and PTF1A loci were detected. CONCLUSION: Nearly one-quarter of Indian children with islet antibody-negative T1DM had recessive mutations in the WFS1 gene. These patients did not exhibit other features of WS at the time of diagnosis. Testing for monogenic diabetes, especially WS, should be considered in Indian children with antibody-negative T1DM.

Double blind randomized control study of intramuscular vitamin D3 supplementation in tropical calcific pancreatitis.

Vitamin D deficiency is prevalent in chronic pancreatitis (CP), but the optimal route and dose of vitamin D supplementation are unknown. We evaluated the relative efficacy of two different doses of intramuscular (i.m.) vitamin D(3) in patients with CP and vitamin D insufficiency. In a double-blind randomized study, 40 patients with tropical calcific pancreatitis with serum 25-hydroxyvitamin D (25OHD) <75 nmol/L (mean 27.0 ± 14.5 nmol/L, <50 nmol/L in 90 %) were divided into three groups. Groups 1 and 2 received 600,000 IU (15,000 µg) and 300,000 IU (7,500 µg) i.m. cholecalciferol, respectively, while group 3 received i.m. saline. All groups received 1 g calcium and 500 IU (12.5 µg) vitamin D(3) orally daily and were studied for 9 months. The primary outcome was the proportion of patients with vitamin D sufficiency (25OHD >75 nmol/L) at 6 months. Vitamin D sufficiency was significantly different in the three groups (85, 29, and 0 % in groups 1, 2, and 3, respectively; p < 0.001). Mean 25OHD remained >75 nmol/L in months 1-6 in group 1 but reached a lower level (50-75 nmol/L) at these time points in group 2. At 6 months, serum alkaline phosphatase decreased significantly only in group 1 (230 ± 73 vs 165 ± 39 IU/L, p = 0.004). No patient in any group developed hypervitaminosis D or hypercalcemia. In conclusion, in patients with CP, a single i.m. injection of 600,000 IU was more effective at achieving vitamin D sufficiency over 6 months compared with 300,000 IU vitamin D(3). (Clinical Trials.gov number NCT00956839).

Etiology, clinical characteristics and mortality among Indian patients with Addison's disease.

The etiology, presentation and mortality of patients with primary adrenal insufficiency (PAI) in developing countries may differ from economically developed nations. However, information in this regard is scanty. The aim of this study was to determine the etiology and compare the clinical characteristics and mortality in infectious and autoimmune causes of PAI in Indian patients. All eligible (n = 89) patients (ages 15-83 years) diagnosed with PAI between 2006 and 2019 were studied. Patients were followed for a median duration of 5.9 (range 0.1-15.7) years. Eighty-six subjects underwent an abdominal computerized tomography scan or ultrasonography, and adrenal biopsy was performed in 60 patients. The most frequent etiologies of PAI were adrenal histoplasmosis (AH, 45%), adrenal tuberculosis (AT, 15%), autoimmunity (AI, 25%) and primary lymphoma (6%). Forty-two percent of patients presented with an acute adrenal crisis. AH and AT could not be differentiated on the basis of clinical features, except for a greater frequency of hepatomegaly-splenomegaly and type 2 diabetes mellitus (63% vs 15%, P < 0.01) in the former. Patients with an autoimmune etiology had a higher frequency of 21-hydroxylase antibodies (41% vs 3%) and autoimmune thyroid disease (46% vs 5%) vs those with infectious etiologies. Mortality was significantly higher in AH (45%) compared with AT (8%) or AI (5%) (P = 0.001). Causes of death included adrenal crises, progressive AH and unexplained acute events occurring at home. In conclusion, infections, especially AH, were the most frequent cause of PAI in north India. Despite appropriate therapy, AH had very high mortality as compared with AT and AI.